Development of a first-in-class antifungal agent to treat Candidiasis and Candidemia

Johns Hopkins University, Baltimore MD

Investigators

Abstract

SUMMARY Multidrug resistant (MDR) yeasts of the genus Candida cause life-threatening nosocomial infections in the US and globally and new antifungal drugs are urgently needed to combat this threat. We have identified a terpenoid natural product (NP; M743) which inhibits an early step in glycosylphosphatidylinositol (GPI) anchoring of mannoproteins to the fungal cell wall. Clinical development of fosmanogepix (FMGX), which inhibits another enzyme in this same process, provides strong clinical validation for the GPI biosynthetic pathway as a novel target for new antifungals. M743 displays potent in vitro antifungal activity across all clinically relevant Candida spp. tested. M743 is shown to be chemically tractable and a semi-synthetic derivative (M720) demonstrates efficacy in a murine model of disseminated Candidiasis and an acceptable preliminary cytotoxicity profile, with its lethal dose (LD50) exceeding 300 mg/kg by IP administration in mice. We propose to develop a first-in-class intravenous (IV)-administered antifungal agent to treat life-threatening Candidemia and Candidiasis infections caused by MDR Candida albicans, C. auris, C. glabrata and lesser prevalent Candida species. Specific Aims. Aim 1. NP Studies to Support M743 Development. M743 fermentation and isolation, whole genome sequencing, scale up, identify and characterize congeners, and genetic engineering of the biosynthetic gene cluster for strain improvements and downstream production of M743 and its de-acylated precursor. Milestone 1. M743 production requirements involve i-ii) 1.5 g of M743 and genome sequence of producer, iii) structure elucidation of congeners for SAR studies, and iv) strain improvements to provide de-acylated precursor of M743 in large scale (>10 g/ batch). Aim 2. Lead Optimization and Preclinical Candidate (PCC) Selection. Synthesize and characterize up to 200 new analogs emphasizing optimization in antifungal potency, target- selectivity, frequency of resistance (FOR) reduced serum binding and cytotoxicity, parenteral PK, PKPD index, and efficacy in a neutropenic murine Candidiasis infection models of C. albicans, C. auris, and C. glabrata. Milestone 2. Identify 2 compounds demonstrating the following favorable attributes i) Mcd4-selective activity, ii) MIC90 < 1 ug/mL vs Candida spp. iii) acceptable FOR (<1 x 109), iv) in vitro therapeutic index (TI) versus human cell lines (TI>128-fold) and no red blood cell (RBC) lysis (RBC> 128 ug/mL), v) reduced ppb (< 95%) and no PANLABS off-target activity (IC50>10 uM), vi) improved PK suitable for IP bid dosing, defined PKPD index, and vii) successful dose ranging studies to guide dose selection. The top 2 analogs achieving dose dependent efficacy in these infection models (defined as > 3 log reduction in fungal burden) and overall favorable drug-like properties will be selected as a PCC and back-up. Aim 3. Safety, Metabolism, PK, and Toxicology. Safety assessment of the PCC using non-GLP material to de-risk the program before GLP material is available to conduct more extensive IND-enabling toxicology studies. Milestone 3: Demonstrate a safe in vivo therapeutic index based on the determined NOAEL in Aim 3 and effective efficacy by IP dosing regimen identified in Aim 2.